atogepant: prescribing information – dosing, contraindications, interactions, side effects

AQUIPTA is indicated for:
• Acute treatment of migraine with or without aura in adults
• Prophylaxis of migraine in adults who have at least 4 migraine days per month.

Posology

The maximum dose per day is 60 mg atogepant.

For acute treatment of migraine as needed, the recommended dose is 60 mg atogepant.

For prophylaxis of migraine, the recommended dose is 60 mg atogepant once daily.

The tablets can be taken with or without meals.

Missed dose

For migraine prophylaxis, a missed dose should be taken as soon as it is remembered. If it is forgotten for an entire day, the missed dose should be skipped and the next dose taken as scheduled.

Dose modifications

Dosing modifications for concomitant use of specific medicinal products are provided in Table 1 (see section 4.5).

Table 1: Dose modifications for interactions
Dose modifications
Recommended once daily dose
Strong CYP3A4 inhibitors
10 mg
Strong OATP inhibitors
10 mg

Special populations

Elderly

Population pharmacokinetic modelling suggests no clinically significant pharmacokinetic differences between elderly and younger subjects. No dose adjustment is needed in elderly patients.

Renal impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment (see section 5.2). In patients with severe renal impairment (creatinine clearance [CLcr] 15-29 mL/min), and in patients with end-stage renal disease (ESRD) (CLcr < 15 mL/min), the recommended dose is 10 mg once daily. For patients with ESRD undergoing intermittent dialysis, AQUIPTA should preferably be taken after dialysis.

Hepatic impairment

No dose adjustment is recommended for patients with mild or moderate hepatic impairment (see section 5.2). Atogepant should be avoided in patients with severe hepatic impairment.

Paediatric population

The safety and efficacy of atogepant in children (< 18 years of age) have not yet been established. No data are available.

Method of administration

AQUIPTA is for oral use. Tablets should be swallowed whole and should not be split, crushed, or chewed.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4).

Summary of the safety profile

Safety was evaluated in 3 852 patients with migraine who received at least one dose of atogepant in clinical studies. Of these, 1 225 patients were exposed to atogepant for prophylaxis daily for at least 6 months and 826 patients were exposed for 12 months. 895 patients were exposed during 24 weeks on an as-needed basis for treatment of acute migraine attacks.

In 12-week, placebo-controlled prophylaxis clinical studies, 678 patients received at least one dose of atogepant 60 mg once daily, and 663 patients received placebo. In the placebo-controlled clinical study for acute treatment of migraine, 1 195 patients received at least one dose of atogepant 60 mg, and 1 177 patients received placebo; patients received both atogepant and placebo to treat qualifying migraines.

In placebo-controlled prophylaxis studies, the most commonly reported adverse reactions were nausea (9%), constipation (8%), and fatigue/somnolence (5%). Most of the reactions were mild or moderate in severity. The adverse reaction that most commonly led to discontinuation for prophylaxis was nausea (0.4%). Nausea (1.3%) was the most commonly reported adverse reaction for acute treatment.

Tabulated list of adverse reactions

Adverse reactions reported in clinical trials and from post-marketing experience are listed below by system organ class and frequency, most frequent reactions first. Frequencies are defined as follows:
very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 2: Adverse reactions identified with atogepant
System organ class
Frequency
Adverse reaction
Acute treatment of migraine
Gastrointestinal disorders
Common
Nausea
Investigations
Uncommon
ALT/AST increased**
Prophylaxis of migraine
Immune system disorders
Not known
Hypersensitivity (e.g., anaphylaxis, dyspnoea, rash, pruritus, urticaria, facial oedema) Metabolism and nutrition disorders Common Decreased appetite Gastrointestinal disorders Common Nausea Constipation General disorders and administration site conditions Common Fatigue/somnolence Investigations Common Weight decreased*

Uncommon
ALT/AST increased**
* Defined in clinical trials as weight decrease of at least 7% at any point.
** Cases of ALT/AST elevations (defined as ≥ 3 × upper limit of normal) temporally associated with atogepant were observed in clinical trials, including cases with a potential positive dechallenge history that resolved within 8 weeks of discontinuation. However, the overall frequency of liver enzyme elevations was similar in the atogepant and placebo groups.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Serious hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylaxis, dyspnoea, rash, pruritus, urticaria, and facial oedema, have been reported with use of AQUIPTA (see section 4.8). Most serious reactions have occurred within 24 hours of first use, however, some hypersensitivity reactions can occur days after administration. Patients should be warned about the symptoms associated with hypersensitivity. If a hypersensitivity reaction occurs, discontinue AQUIPTA and institute appropriate therapy.

Hepatic impairment

Atogepant is not recommended in patients with severe hepatic impairment (see section 4.2).

Excipients with known effect

AQUIPTA 10 mg tablets contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

AQUIPTA 60 mg tablets contain 31.5 mg sodium per tablet, equivalent to 1.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

CYP3A4 inhibitors

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) can significantly increase systemic exposure to atogepant. Co-administration of atogepant with itraconazole resulted in increased exposure (Cmax by 2.15-fold and AUC by 5.5-fold) of atogepant in healthy subjects (see section 4.2). Changes in atogepant exposure when co-administered with weak or moderate CYP3A4 inhibitors are not expected to be clinically significant.

Transporter inhibitors

Organic anion transporting polypeptide (OATP) inhibitors (e.g., rifampicin, ciclosporin, ritonavir) can significantly increase systemic exposure to atogepant. Co-administration of atogepant with single dose rifampicin resulted in increased exposure (Cmax by 2.23-fold and AUC by 2.85-fold) of atogepant in healthy subjects (see section 4.2).

Frequently co-administered medicinal products

Co-administration of atogepant with oral contraceptive components ethinyl estradiol and levonorgestrel, paracetamol, naproxen, sumatriptan, or ubrogepant did not result in significant pharmacokinetic interactions for either atogepant or co-administered medicinal products. Co- administration with famotidine or esomeprazole did not result in clinically relevant changes of atogepant exposure.

Pregnancy

There are limited data from the use of atogepant in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Atogepant is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

Pharmacokinetic data after single-dose administration showed minimal transfer of atogepant into breast milk (see section 5.2).

There are no data on the effects of atogepant on the breastfed infant or the effects of atogepant on milk production.

The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for atogepant and any potential adverse effects on the breastfed infant from atogepant or from the underlying maternal condition.

Fertility

No human data on the effect of atogepant on fertility are available. Animal studies showed no impact on female and male fertility with atogepant treatment (see section 5.3).

Atogepant has no or negligible influence on the ability to drive and use machines. However, it may cause somnolence in some patients. Patients should exercise caution before driving or using machinery until they are reasonably certain that atogepant does not adversely affect performance.

In clinical studies, atogepant was administered as single doses up to 300 mg and as multiple doses up to 170 mg once daily. Adverse reactions were comparable to those seen at lower doses, and no specific toxicities were identified. There is no known antidote for atogepant. Treatment of an overdose should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Analgesics, calcitonin gene-related peptide (CGRP) antagonists, ATC code: N02CD07

Mechanism of action

Non-clinical receptor binding studies and in vitro functional studies point to an involvement of more than one receptor type in the pharmacological effects of atogepant. Atogepant shows affinity to several receptors of the calcitonin/CGRP-receptor family. In view of the clinically relevant free plasma concentrations of atogepant (Cmax > 20 nM for a 60 mg dose) and the fact that CGRP and amylin-1 receptors are considered to be involved in the pathophysiology of migraine, inhibitory effects of atogepant at these receptors (Ki-value 26 pM and 2.4 nM, respectively) could be of clinical relevance.
However, the precise mechanism of action of atogepant in the prophylaxis or treatment of migraine remains to be established.

Clinical efficacy and safety

Acute treatment of migraine

The efficacy of AQUIPTA for the acute treatment of migraine with or without aura in adults was studied in a randomised, double-blind, placebo-controlled study (ECLIPSE). In the 16-week blinded treatment period, 1 328 subjects were randomised to 1 of 4 sequence groups to treat 4 qualifying migraine attacks of moderate or severe headache pain intensity with either atogepant 60 mg (3 attacks) or placebo (1 attack) in a prespecified order. Subjects who completed the blinded period of the study treated subsequent attacks with open-label atogepant 60 mg until the end of week 24. Approximately 22% of subjects were using concomitant migraine-prophylaxis medication (e.g., topiramate, amitriptyline, propranolol). Rescue medication was permitted beginning 2 hours after taking study drug. The use of a concomitant medicinal product that acts on the CGRP pathway was not permitted for either acute or preventive treatment of migraine.

During the double-blind study period, 1 037 subjects treated 4 qualifying migraine attacks. Mean migraine frequency was approximately 4 moderate to severe migraine attacks per month over the 3 months prior to enrolment.

The primary efficacy endpoint was pain freedom (defined as reduction in headache severity from moderate/severe to no pain) at 2 hours during Attack 1 (Table 3). Secondary endpoints included absence of patient-identified most bothersome symptom at 2 hours, pain relief (defined as reduction in headache severity from moderate/severe to mild/no pain) at 2 hours, and sustained pain freedom from 2 hours to 48 hours. AQUIPTA demonstrated statistically significant and clinically meaningful improvement for these endpoints compared to placebo. In addition, statistically significant effects were demonstrated for secondary endpoints of use of rescue medication within 24 hours and ability to function normally at 2 hours.

Table 3: Efficacy endpoints during Attack 1 in ECLIPSE

AQUIPTA 60 mg
N=602
Placebo
N=612
Pain-free at 2 hours

% Responders

Absorption

Following oral administration, atogepant is absorbed with peak plasma concentrations at approximately 1 to 2 hours. Following once daily dosing, atogepant displays dose-proportional pharmacokinetics up to 170 mg (approximately 3 times the highest recommended dose), with no accumulation.

Effect of food

When atogepant was administered with a high-fat meal, AUC and Cmax were reduced by approximately 18% and 22%, respectively, with no effect on median time to maximum atogepant plasma concentration. Atogepant was administered without regard to food in clinical efficacy studies.

Distribution

Plasma protein binding of atogepant was not concentration-dependent in the range of 0.1 to 10 µM;
the unbound fraction of atogepant was approximately 4.7% in human plasma. The mean apparent volume of distribution of atogepant (Vz/F) after oral administration is approximately 292 L.

Biotransformation

Atogepant is eliminated mainly through metabolism, primarily by CYP3A4. The parent compound (atogepant), and a glucuronide conjugate metabolite (M23) were the most prevalent circulating components in human plasma.

CYP3A4 inducers

Co-administration of atogepant with steady state rifampicin, a strong CYP3A4 inducer, resulted in a significant decrease in exposure (Cmax by 30% and AUC by 60%) of atogepant in healthy subjects.

Co-administration of atogepant with steady-state topiramate, a mild CYP3A4 inducer, resulted in a decrease in exposure (Cmax by 24% and AUC by 25%) of atogepant.

In vitro, atogepant is not an inhibitor for CYP3A4, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, MAO-A, or UGT1A1 at clinically relevant concentrations. Atogepant also is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.

Elimination